Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• This invention relates to novel (N- phthalimidoalkyl) piperidine compounds, pharmaceutical compositions containing them and methods of using these compounds and compositions to treat physiological or drug induced psychoses in mammals and also as
• R 1 denotes a univalent group derived from one selected among substituted or unsubstituted benzene, pyridine, pyrazine, indole, anthraquinone,
• quinoline substituted or unsubstituted phthalimide including specifically:
• pyridinecarboxylic acid imide pyridine N-oxide, pyrazinedicarboxylic acid imide, substituted or unsubstituted quinazolinedione and pyromerylimide;
• X denotes a group of the formula -(CH 2 ) n -, -O(CH 2 )n-,
• n is an integer of 1 through 7 and R 3 represents a lower alkyl group or a benzyl group);
• ring A denotes a group of the formula.
• R 2 denotes hydrogen, lower alkyl, substituted or
• X is halogen or trifluoromethyl
• R 1 and R 2 are independently hydrogen, lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylthio, trifluoromethyl, cyano, or nitro;
• Y is a single bond or a divalent straight or branched chain alkylene radical of 1 to 4 carbon atoms inclusive.
• GB 1,425,578 discloses compounds of the formula:
• R 1 is hydrogen, alkyl, aralkyl or alkyl substituted by a heterocyclyl group
• R 2 and R 3 which may be the same or different, are
• These compounds are disclosed as having anti- convulsant activity and in some cases, anti-inflammatory activity or anti-arrhythmic activity.
• R 0 and R 1 are the same or different and are each
• R 2 is selected from hydrogen, halogen, alkyl having 1, 2, or 3 carbon atoms, alkoxy having 1, 2, or 3 carbon atoms, and trifluoromethyl.
• antipsychotic agents have been potent dopamine receptor antagonists.
• phenothiazines such as chlorpromazine and most butyrophenones such as
• haloperidol are potent dopamine receptor antagonists.
• dopamine receptor antagonists are associated with a high incidence of side effects, particularly
• Parkinson-like motor effects or extra-pyramidal side- effects EPS
• dyskinesias including tardive dyskinesias at high doses.
• Many of these side effects are not reversible even after the dopamine receptor antagonist agent is discontinued.
• the present invention is related to antipsychotic agents which are selective antagonists for the sigma receptor. Unlike dopamine receptor blockers known in the art, the compounds of the present invention have low potential for the typical movement disorder side-effects associated with the dopamine antagonist antipsychotic agents while they maintain the ability to antagonize aggressive behavior and antagonize hallucinogenic- induced behavior.
• the sigma-selective antipsychotic compounds of the present invention are (N-phthalimidoalkyl) piperidines of the formula:
• a is a single or double bond, provided that when a is a double bond then R 2 (CH 2 ) n is attached at C-4 and
• n is 0-4, provided that when (CH 2 ) n R 2 is attached to the 2-position of the piperidine ring then n is 2-4;
• R 1 is (CH 2 ) m R 3 or (CH 2 ) p Ar, where m is 1-4 and p is 1-4;
• R 3 is cycloalkyl of 3 to 8 carbon atoms
• R 4 is 1-4 substituents independently selected from the group consisting of H, halogen, NO 2 , NH 2 , haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, C 1 -C 3 alkyl, NHCOR 7 , NHCO-phenyl, OH, OR 8 and Ar';
• R 7 and R 8 independently are H or alkyl of 1 to 3 carbon atoms;
• X is O; H 2 ; H, OH; R 9 , OH; Ar'", OH; H, R 9 ; or H, OR 9 ;
• Y is CH 2 , CHR 10 , C(R 10 ) 2 . O, CH 2 CH 2 , (CH 2 )3,
• Ar, Ar', Ar'' and Ar''' independently are phenyl
• halogen OH, alkoxy of 1 to 3 carbon atoms, NR 11 R 12 , SH, S(O) t R 13 , where t is 0-2, haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, alkyl of 1 to 3 carbon atoms, CO 2 H, carboalkoxy of 2 to 6 carbon atoms, CN, NO 2 , SO 2 NH 2 , SO 3 H, CO 2 NR 14 R 15 or phenyl;
• R 9 and R 10 independently are alkyl of 1 to 3 carbon
• R 11 -R 15 independently are H or alkyl of 1 to 3 carbon atoms
• R 16 is H, OH, O-alkyl of 1-6 carbons, O-acyl of 1-8
• dialkylamino where alkyl and alkoxy are from 1- 12 carbons and aryl is from 6-12 carbons
• 2- and 3-pyrrolyl 2- and 3- furyl, 2- and 3- thienyl, 2, 3, and 4-pyridyl, 2- and 3-benzolfur- 1 , 2- and 3- indolyl, 2- and 3- benzothienyl, 2, 3, and 4- quinolyl, and 1, 3, and 4-isoquinolyl;
• R 2 cannot be : if X is O; H 2 ; or H, OH;
• X cannot be H 2 or O
• R 2 is attached at the C-3 or C-4 position of the piperidine ring; and where R 4 is H, halogen, CF 3 , alkyl, alkoxy, NH 2 ,
• Some compounds of the present invention can exist as optical isomers and both the racemic mixtures of these isomers as well as the individual optical isomers which confer activity are within the scope of the present invention.
• the racemic mixtures can be
• Preferred compounds of the present invention are compounds of formula (I) wherein:
• n 1-4;
• R 1 is (CH 2 )pAr
• p is 1-2;
• X is O or H 2 ;
• R 4 , R 5 and R 6 are all H;
• Ar is phenyl
• Y is (CH 2 ) 3 or O.
• More preferred compounds of the present invention are the compounds of formula (I) wherein n is 1.
• n 1;
• X is O
• R 4 is H
• R 1 is (CH 2 ) p Ar
• Ar is phenyl.
• (CH 2 ) n R 2 is attached at the C-4 position of the piperidine ring;
• n 1;
• X is O
• Y is (CH 2 ) 3 ;
• R 5 and R 6 are H
• R 1 is (CH 2 ) p Ar
• Ar is phenyl
• n 1;
• X is O
• Y is O
• R 5 and R 6 are H
• R 1 is (CH 2 ) p Ar
• Ar is phenyl. (4 ) (CH 2 ) n R 2 is attached at the C-4 position of the piperidine ring;
• n 1;
• X is H 2 ;
• R 4 is H
• R 1 is (CH 2 ) p Ar
• Ar is phenyl
• compositions and methods of using them for the treatment of physiological or drug induced psychosis or dyskinesia in a mammal comprising a pharmaceutically
• a is a single or double bond, provided that when a is a double bond, then R 2 (CH 2 ) n is attached at C-4 and
• n is 0-4, provided that when (CH 2 ) n R 2 is attached to the
• n 2-position of the piperidine ring then n is 2-4;
• R 1 is (CH 2 ) m R 3 or (CH 2 ) p Ar, where m is 1-4 and p is 1-4;
• R 3 is cycloalkyl of 3 to 8 carbon atoms
• R 4 is 1-4 substituents independently selected from the group consisting of H, halogen, NO 2 , NH 2 , haloalkyl of 1 to 3 carbon atoms and 1 to 7 halogen atoms, C 1 -C 3 alkyl, NHCOR 7 , NHCO-phenyl, OH, OR 8 and Ar';
• X is O; H 2 ; H, OH; R 9 , OH; Ar'", OH; H, R 9 ; or H, OR 9 ;
• Y is CH 2 , CHR 10 , C(R 10 ) 2 , O, CH 2 CH 2 , (CH 2 )3,
• Ar, Ar', Ar'' and Ar''' independently are phenyl
• halogen OH, alkoxy of 1 to 3 carbon atoms, NR 11 R 12 , SH, S(O) t R 13 .
• t is 0-2, haloalkyl of 1 'to 3 carbon atoms and 1 to 7 halogen atoms, alkyl of 1 to 3 carbon atoms, CO 2 H, carboalkoxy of 2 to 6 carbon atoms, CN, NO 2 , SO 2 NH 2 , SO 3 H, CO 2 NR 14 R 15 or phenyl;
• R 9 and R 10 independently are alkyl of 1 to 3 carbon
• R 11 -R 15 independently are H or alkyl of 1 to 3 carbon atoms
• R 16 is H, OH, O-alkyl of 1-6 carbons, O-acyl of 1-8
• perfluoroalkoxy, perfluoroalkylthio, and dialkylamino where alkyl and alkoxy are from 1- 12 carbons and aryl is from 6-12 carbons
• the two reactions of Scheme A may be carried out in a single step by heating amines 1 with anhydrides corresponding to R 2 (where N- is replaced by 0) in high-boiling solvents, such as dimethylformamide or ethylene glycol dimethyl ether, or without solvents to temperatures of about 140 to 200°.
• high-boiling solvents such as dimethylformamide or ethylene glycol dimethyl ether
• the amines 1 and the anhydrides corresponding to R 2 where N- is replaced by 0 are known in the literature or can be prepared by standard methods: Harper, N.J., Chignell, C.F.; J. Med. Chem. 1964. 7, 729; Abou- Gharbia, M., et al., ibid., 1988. 31, 1382.
• amines 1 are replaced by the corresponding pyridine derivatives 2.
• intermediates of type A are then reacted with an alkylating agent of type R 1 Z, where Z is Cl, Br, I or an activated ester group such as OSO 2 -alkyl or OSO 2 -aryl, at temperatures of about 0 to 200°C in solvents such as ether, tetrahydrofuran, acetonitrile, alcohols such as ethanol or n-butanol, or dimethylformamide.
• solvents such as ether, tetrahydrofuran, acetonitrile, alcohols such as ethanol or n-butanol, or dimethylformamide.
• the quaternary pyridinium salts of type 5. so obtained are then reduced to the compounds of the invention by treatment with hydrogen in the presence of a catalyst such as platinum at temperatures of about 0 to 200oC and hydrogen pressures of 1-100 atm.
• Amines 3 are known in the literature or can be prepared by standard methods: Satoh, T. and Suzuki, S., Tetrahedron Lett., 1969, 4555. Method C
• Imides, R 2 H are treated with a base, such as sodium hydride or potassium hydride in aprotic solvents such as tetrahydrofuran, dimethylformamide or
• the imides R 2 H are known in the literature or can be prepared from the corresponding anhydrides by methods well known in the literature: Kitahonoki, K;
• Amines of type 1 are allowed to react with maleic anhydride or maleic anhydrides substituted with one or two R 4 groups to give maleamic acids of type 10.
• the latter are converted into the maleimides of type 11 by well-known methods such as those given in Method A.
• the maleimides of type 11 are then subjected to the Diels-Alder reaction with dienes listed below which are optionally substituted with R 5 and R 6 in solvents such as tetrahydrofuran, acetonitrile, or aromatic hydrocarbons such as toluene or xylene, or chlorinated aromatic hydrocarbons such as chlorobenzene or dichlorobenzene; at temperatures of 0- 250°C and pressures of 1-15,000 atm. to give certain compounds of this invention.
• the Diels-Alder reaction is optionally carried out in the presence of a radical inhibitor such as hydroquinone or phenothiazine to prevent polymerization of the dienes.
• the products of the Diels-Alder reaction are optionally subjected to catalytic hydrogenation in solvents such as tetrahydrofuran, ethyl acetate, or ethanol, with catalysts such as palladium or platinium, at temperatures of about 0 to 200°C and hydrogen pressures of 1-100 atm. to give certain compounds of this invention as illustrated by the following example:
• a variation of this method uses amines 3, as specified in Method B, as the starting materials.
• the pyridine imides of type 12. obtained in this way are converted into certain compounds of this invention by quaternization followed by reduction as described in Method B.
• the double bond introduced in the Diels- Alder reaction is also reduced in the last step, as illustrated in the following scheme: Scheme D-1
• OR 9 can be prepared as follows: compounds R 2 H react with 2-vinylpyridine or 4-vinylpyridine in the presence of a base such as Triton B or sodium hydride in high- boiling solvents such as N-methylpyrrolidone or. preferably, using the vinylpyridines as solvents, at temperatures of about 100-250°C to give imides of type 13. These are then converted into certain compounds of this invention, as specified above, by quaternization followed by reduction as described in Method B. The following scheme is an illustration of this method.
• Phthalimides may also be reduced to compounds of type 14 by the action of zinc and acetic acid.
• solvents such as tetrahydrofuran, or metal alkoxides such as sodium methoxide in alcohol solvents such as methanol, followed by addition of an alkylating agent R 9 Z where Z is Cl, Br, I; OSO 2 -alkyl or OSO 2 -aryl, at temperatures of about 0-100°C, for instance:
• aluminium hydride in aprotic solvents such as
• arylsulfonyl halides such as methanesulfonyl chloride in solvents such as tetrahydrofuran or methylene chloride in the presence of a base such as pyridine or
• the substituent R 1 can be introduced as described in methods A-E above.
• a protecting group P may be used in place of R 1 .
• the group P is removed at the end of the synthesis ana replaced by R 1 .
• a benzyl group may be used as shown in the following example.
• the benzyl group may be then replaced by hydrogen using well-known methods such as hydrogenolysis in the presence of a catalyst such as palladium and the R 1 group may be introduced by treating the secondary amine with alkylating agents R 1 z where Z is Cl, Br, I, OSO 2 -alkyl or OSO 2 -aryl in the presence of a base such as alkali carbonates at temperatures of about 0 to 150°C in solvents such as acetonitrile or dimethylformamide.
• a catalyst such as palladium
• R 1 group may be introduced by treating the secondary amine with alkylating agents R 1 z where Z is Cl, Br, I, OSO 2 -alkyl or OSO 2 -aryl in the presence of a base such as alkali carbonates at temperatures of about 0 to 150°C in solvents such as acetonitrile or dimethylformamide.
• a methyl group may serve as a protecting group P. It may be removed by well-known methods such as reaction with cyanogen bromide followed by hydrolysis, or reaction with alkyl chloroformates followed by hydrolysis.
• unsaturated alcohols 21 These are then coupled to imides R 2 H by reaction with triphenylphosphine and diethyl azodicarboxylate in anhydrous solvents such as tetrahydrofuran at temperatures of -20° to 60°
• Example 1 The invention can be further understood by the following examples in which temperatures are in degrees Centigrade and parts and percentages are by weight unless otherwise indicated.
• Example 1 Example 1
• the fumaric acid salt had m.p. 179-181° after crystallization from 2-propanol.
• NMR (CDCl 3 :DMSO-d 6 ) : ⁇ 7.04-7.34 (m, 5H); 6.63 (s, 2H); 5.78-5.90 (s, 2H);
• the fumaric acid salt had m.p. 151-152° after crystallization from 2-propanol.
• the fumaric acid salt had m.p. 211-213°C after crystallization from 2-propanol.
• the salt with fumaric acid had m.p. 211-212° after crystallization from 2-propanol. Anal. Calcd. for
• the fumaric acid salt had m.p. 219-221° after crystallization from 2-propanol.
• N denotes the carbon atom of the piperidine ring to which the (CH 2 ) n R 2 group is attached.
• R 16 ph; R 2 (CH 2 ) n attached to C-4 of the piperidine).
• the fumaric acid salt had m.p. 185° after
• PCP phencyclidine
• Brain membranes were prepared by the method of Tarn (Proc. Natl. Acad. Sci. USA 80: 6703-6707, 1983).
• Whole brains were homogenized (20 sec.) in 10 vol (wt/vol) of ice-cold 0.34 M sucrose with a Brinkmann Polytron (setting 8). The homogenate was centrifuged at 920 x g for 10 min. The supernatant was centrifuged at 47,000 x g for 20 min.
• the resulting membrane pellet was resuspended in 10 vol (original wt/vol) of 50 mM Tris HCl (pH 7.4) and incubated at 37°C for 45 min to degrade and dissociate bound endogenous ligands. The membranes were then centrifuged at 47,000 x g for 20 min and resuspended in 50 mM Tris HCl (50 mL per brain).
• IC 50 S were calculated from log-logit plots.
• K i IC 50 /[1 + (L/K d ) ] (4), where L is the concentration of radioligand and K d is its dissociation constant. Data are shown in Table I.
• Membranes were prepared from guinea pig striatum by the method described for sigma receptor binding. The membranes were then resuspended in 50 mM Tris HCl (9 mL per brain).
• Nonspecific binding was measured in the presence of 100 nM (+)-butaclamol. After 15 min of incubation at 37°C, samples were filtered rapidly through Whatman GF/C glass filters under negative pressure, and washed three times with ice-cold binding buffer (5 mL). Data are shown in Table I.
• haloperidol a typical antipsychotic drug
• This binding profile of haloperidol reflects the therapeutic activity as well as the motor side effects caused by antagonism of the dopamine receptors.
• the examples of this invention shown in Table I indicate potent and selective binding affinity for sigma receptors without binding to the dopamine receptors. Therefore these compounds are not expected to produce the extrapyramidal symptoms that are typical of that produced by
• mice Male Balb/c mice (Charles River) were used. After 2 weeks of isolation in plastic cages (11.5 x 5.75 x 6 in) the mice were selected for aggression by placing a normal group-housed mouse in the cage with the isolate for a maximum of 3 min. Isolated mice failing to consistently attack an intruder were eliminated from the colony.
• Drug testing was carried out by treating the isolated mice with test drugs or standards. Fifteen min after dosing with drugs by the oral route (po), one isolated mouse was removed from its home cage and placed in the home cage of another isolate. Scoring was a yes or no response for each pair. A maximum of 3 min was allowed for an attack and the pair was separated
• mice were treated and tested twice a week with at least a 2 day washout period between treatments.
• mice Male Sprague-Dawley rats (CD/CR, Charles River), weighing 190-290 g, were used for surgery. In order to spare nonadrenergic neurons, rats were injected with 25 mg/kg imipramine intraperitoneal (i.p.) 30 min before surgery. The rats were anesthetized with a 1:1.2 ratio mixture of Xylazine:Ketamine given 0.1 mL/100 g body weight intramuscular (i.m.). A Ringers-Wydaze
• Stereotaxic injection coordinates were -2.5 mm posterior to bregma, -2.1 mm right of the midsagittal suture, and -8.6 mm below the skull surface with the incisor bar set at +5.0 mm. Following surgery they were given 10 days to recover while housed four per cage (45.0 L x 20.0 H x 26.0 W) with ALPHA-dri bedding and ad lib access to Pro-Lab rodent chow and deionized water. Following recovery, the wood clips were removed, the rats were individually housed in suspended cages, and they were placed on a restricted diet so that their weight did not exceed 375 g. At all times they were housed in the animal care facility under a 12-12 hour light/dark cycle (light on at 6:00 h, light off at 18:00 h).
• Rotation rate and direction were determined with Coulbourn Instruments Rotometry Monitors. Clockwise and counter clockwise rotations were recorded at 30 and 60 min intervals. The rats were examined for correct lesion location by testing for rotational activity induced by subcutaneous (s.c.) injections of 3.0 mg/kg D-amphetamine SO 4 , and 2.0 mg/kg PCP HCl, respectively. These drugs were administered in the following sequence: Amphetamine was given 30 sec before testing. Seven days later, the rats were injected with PCP 30 sec before testing. Only those rats with an ipsilateral rotation rate of 2.5 turns per min or higher were used in
• Methocel ® or test drugs were administered p.o. 20 min before testing. Phencyclidine (1.5 mg/kg) was given s.c. immediately before testing.
• the data was analyzed with an analysis of variance statistical test, and individual comparisons of each dose of test drug to control were made with Dunnett's multiple range test.
• the ED 50 was calculated with a Litchfield and Wilcoxon test using percent of control values. Data are shown in Table III.
• Example 3 does not produce catalepsy and suggests very low potential for extrapyramidal symptoms and tardive dyskinesia.
• Dosage forms (compositions) suitable for administration ranges from 1 mg to 2000 mg.
• the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally in sterile liquid dosage forms.
• Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric- coated for selective disintegration in the
• Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
• water a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
• saline aqueous dextrose (glucose)
• glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
• Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
• suitable stabilizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
• citric acid and its salts and sodium EDTA are suitable stabilizing agents.
• parenteral solutions can contain
• preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

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